Targeting isoprenoid biosynthesis is a potentially important route for antibiotic discovery because isoprenoids are involved in the very early steps of bacterial cell wall biosynthesis, including the condensation of dimethylallyl diphosphate (DMAPP, 1) with two molecules of isopentenyl diphosphate (IPP, 2) to form farnesyl diphosphate (FPP, 3), catalyzed by the enzyme farnesyl diphosphate synthase (FPPS), followed by the addition of 8 more IPP molecules to form undecaprenyl diphosphate (UPP, 4); FIG. 1. Formation of UPP (4) is catalyzed by the enzyme undecaprenyl diphosphate synthase (UPPS), and several moderate UPPS inhibitors are known. UPP is then hydrolyzed to the monophosphate, which is next converted to Lipid I and Lipid II, leading to formation of cell wall peptidoglycan; FIG. 1.
The UPPS structure is unusual in that there are four known ligand binding sites, opening up the possibility of designing a diverse range of inhibitors. UPPS inhibitors could act synergistically with cell wall biosynthesis inhibitors to reduce the toxicity of drugs such as vancomycin (by decreasing dosage), or to restore drug sensitivity (e.g., with methicillin-resistant Staphylococcus aureus (MSRA)). Antibiotics such as methicillin and vancomycin act in the latter stages of peptidoglycan formation, as shown in FIG. 1. However, new UPPS inhibitors are needed because UPPS is an essential microbial enzyme not present in humans.